The long-term goal of our laboratory's research is to develop technologies to replace kidney tissue in children and adults with irreversible kidney damage, resulting from the loss of nephrons. At present, irreversible kidney damage leads to dialysis and transplantation, situations that carry with them considerable morbidity and mortality and cost the health care system well over 10 billion dollars annually. As nephrons are composed of at least 15 distinct cell types, arranged into a highly specialized architecture, the most feasible approach to generating new nephrons is to be able to manipulate kidney stem-progenitor cells, similar to those found in the embryonic kidney, that are genetically programmed to form whole nephrons. There are two crucial aspects that must both be achieved to develop stem cell- based regenerative therapies for irreversible kidney disease. First, it will be necessary to increase our understanding of how kidney stem and progenitor cell populations are maintained and how nephrons differentiate. This is the subject of the present grant. Additionally, it will be necessary to develop approaches to transform embryonic stem cells and induced pluripotent stem (IPS) cells into kidney progenitor cells. Together, achieving these goals will move us closer to a time where individuals suffering from kidney disease will be able to take advantage of the recent great advancements in stem cell research. In this grant, we propose new studies that center on the role of Bone Morphogenetic Proteins (BMPs) and Fibroblast Growth Factors (FGFs) to regulate kidney stem and progenitor cells. We focus on novel pathways through which BMP and FGF signals expressed by the ureteric bud, pretubular aggregate and progenitor cells themselves can regulate progenitor cell populations in the developing nephron. We hypothesize that there are important interactions between these families of growth factors in the developing kidney, similar to what is observed in other developmental systems. PUBLIC HEALTH RELEVANCE: This grant examines the mechanisms by which kidneys develops a set of stem cells that give rise to the mature kidney. Our long-range goal is to harness these cells for eventual regenerative therapies to treat kidney disease in children and adults with irreversible damage to their kidneys, who have chronic renal failure that would otherwise require dialysis or transplantation.